CDR-Grafted Okt4a Monoclonal Antibody in Cynomolgus Renal Allograft Recipients1,2

Powelson, John A.; Knowles, Robert W.; Delmonico, F L; Kawai, T; Mourad, Georges; Preffer, F K; Colvin, R. B.; Cosimi, A. Benedict

doi:10.1097/00007890-199403270-00002

Cited by 24 publications

(10 citation statements)

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“…Interestingly, human IgG4 was also as potent as IgG1 at killing target cells in an in vivo mouse model of immunotherapy [7]. As human IgG4 T cell MoAbs are now being produced as 'blocking' MoAbs for therapeutic use [8], we decided to investigate their in vivo biological activity.…”

Section: Introductionmentioning

confidence: 99%

A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

Isaacs

Wing

Greenwood³

et al. 1996

Clinical and Experimental Immunology

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It is traditionally held that human IgG4 MoAbs should not deplete target cells in vivo, as this isotype is inactive in a number of in vitro assays that measure effector function. We have previously challenged this dogma, and the current study was designed to investigate the in vivo biological effects in humans of a MoAb of human IgG4 isotype. Nine patients with refractory rheumatoid arthritis (RA) fulfilling ARA criteria, and one with ankylosing spondylitis (AS) received a human IgG4 Campath‐1 MoAb (with specificity against the pan‐lymphocyte antigen CD52) as part of a two‐stage therapeutic protocol. In stage 1, patients received a single dose of this MoAb. Stage 2, starting 48 h later, comprised a 5‐day course of a human IgG1 Campath‐1 MoAb with identical V‐region (CAMPATH‐1H), as previously used in the management of RA patients. The intervening 48 h provided a window of opportunity to monitor the biological effects of the IgG4 MoAb for comparison with the IgG1. The two MoAbs were also compared for in vitro biological activity. IgG4 depleted peripheral blood lymphocytes (PBL), albeit less efficiently than IgG1. It produced a first‐dose reaction of similar intensity, although associated circulating tumour necrosis factor‐alpha (TNF‐α) levels were lower. TNF‐α release from whole blood in vitro was also greater with the IgG1 MoAb. The study design did not permit conclusions to be drawn regarding therapeutic efficacy of the IgG4 MoAb. In summary, a human IgG4 Campath‐1 MoAb depletes target cells in vivo. Importantly, this study demonstrates for the first time in humans that in vitro assays may not predict the in vivo effector function of therapeutic MoAbs.

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Section: Introductionmentioning

confidence: 99%

A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

Isaacs

Wing

Greenwood³

et al. 1996

Clinical and Experimental Immunology

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“…However, autologous antibodies can be induced against a variety of fully human biological agents that are used for therapy (39)(40)(41)(42)(43)(44)(45)(46). Depending on their epitope specificity, autoreactive anti-CD4 antibodies have been shown to mediate CD4 ϩ T cell depletion, suppression of T cell-dependent immune responses, or various other forms of immune dysregulation (47)(48)(49)(50)(51)(52)(53)(54), effects that define safety concerns for HIV vaccine testing.…”

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confidence: 99%

An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques

Schwartz

Prado

Misamore

et al. 2016

Clin Vaccine Immunol

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؉ T cell staining, and temporal trends in T cell subset frequencies served to assess whether anti-CD4 autoantibody responses were elicited by vaccination. We find that immunization with multiple high doses of rhFLSC did not elicit detectable antibody titers despite robust responses to rhFLSC. In accordance with these findings, immunized animals had no changes in circulating CD4 ؉ T cell counts or evidence of autoantibody reactivity with cell surface CD4 on primary naive macaque T cells. Collectively, these studies show that antigens using CD4 sequences to stabilize transition state gp120 structures are unlikely to elicit autoimmune antibody responses, supporting the advancement of gp120-CD4 complexbased antigens, such as FLSC, into clinical testing.

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“…Although several anti-CD4 Abs have been evaluated in preclinical non-human primate models of transplant (17,18) and autoimmune disease (19,20) as well as in a number of clinical studies (21-32), their therapeutic effectiveness was modest at best, of short duration, and most likely the consequence of transient immunosuppression. In retrospect, the failure of anti-CD4 Abs to induce a more robust and durable response in primates may be attributed to technical factors relating to both Ab properties and dose.…”

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confidence: 99%

Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody

Winsor-Hines¹,

Merrill²,

O'Mahony³

et al. 2004

The Journal of Immunology

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CDR-Grafted Okt4a Monoclonal Antibody in Cynomolgus Renal Allograft Recipients1,2

Cited by 24 publications

References 0 publications

A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques

Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody

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